As discussed earlier in this chapter, the lipid abnormality that contributes most to CV disease is high LDL cholesterol.
Accordingly, we will focus primarily on drugs for this disorder.
Nonetheless, we also need to consider other lipid abnormalities, especially (1) high total cholesterol,a (2) low HDL cholesterol, and (3) high TGs.
Some drugs for dyslipidemias are more selective than others.
That is, whereas some drugs may improve just one dyslipidemia (e.g., high TGs), others may improve two or more dyslipidemias.
The highly selective agents can be useful as add-ons, to “target”
a particular lipid abnormality when other medications prove inadequate.
Drugs that lower LDL cholesterol levels include HMG-CoA reductase inhibitors (statins), bile-acid sequestrants, and ezetimibe. All are effective to varying degrees. The HMG-CoA reductase inhibitors—the statins—are more effective than the others, cause fewer adverse effects, are better tolerated, and are more likely to improve clinical outcomes.
As we consider the drugs for lipid disorders, you should be aware of the following: Although all of these drugs can improve lipid profiles, not all of them improve clinical outcomes (reduced morbidity and mortality). This leads us to question whether some of the lipid abnormalities are a true cause of pathophysiology and ultimate death, or whether they are simply
“associated markers” of some other pathophysiology that we don’t yet understand.
Prototype Drugs
LDL CHOLESTEROL- AND TRIGLYCERIDE- LOWERING DRUGS
HMG-CoA Reductase Inhibitors (Statins) Lovastatin
Bile-Acid Sequestrants Colesevelam
Others Ezetimibe
aNote that total cholesterol is slightly different from the simple sum of LDL cholesterol (LDL-C) plus HDL cholesterol (HDL-C); triglycerides (TG) also contribute to the value, as in the following equation: total cholesterol = HDL-C + LDL-C + (TG/5) (provided TG levels are below 400 mg/dL).
indicating that (1) inhibition of cholesterol synthesis, by itself, is not sufficient to explain cholesterol-lowering effects; and (2) for statins to be effective, synthesis of LDL receptors must increase.
In addition to inhibiting HMG-CoA reductase, statins decrease production of apolipoprotein B-100. As a result, hepatocytes decrease production of VLDLs. This lowers VLDL levels and TG levels too since they’re the main lipid in VLDLs.
Also, statins raise HDL levels by 5% to 22%.
Clinical Trials
Statins slow the progression of ASCVD and decrease the risk of stroke, hospitalization, cardiac events, peripheral vascular disease, and death. Benefits are seen in men and women, and in apparently healthy people, as well as in those with a history of CV events. Hence, the statins are useful for both primary and secondary prevention. Furthermore, these drugs can help people with even normal LDL levels, in addition to those whose LDL level is high. Statins may also have some added protective effects in people with diabetes.
Secondary Prevention Studies. In patients with evidence of existing ASCVD (angina pectoris or previous MI), statins reduce the risk of death from cardiac causes. This was first demonstrated conclusively in the landmark Scandinavian Simvastatin Survival Study (4S). After 4.9 to 6.3 years of follow-up, the death rate was 12% among patients taking placebo and 8%
among those taking simvastatin—a 30% decrease in overall mortality. Benefits were due to a decrease in cardiac-related mortality; deaths from noncardiac causes were the same in both groups.
The Cholesterol and Recurrent Events (CARE) trial demonstrated the ability of statins to reduce the risk of stroke in addition to coronary events.
In this study, 4159 people with a history of MI were given pravastatin (40 mg daily) or placebo. After 5 years, the incidence of MI (fatal or nonfatal) was 13.2% in those taking placebo and 10.2% in those taking the drug. Pravastatin also produced a 26% decrease in the risk of stroke.
The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE- IT) trial was the first to show that intensive reductions in LDL with statin Nonlipid Beneficial CV Actions. There is increasing
evidence that statins do more than just alter lipid levels. Specifi- cally, they can promote atherosclerotic plaque stability (by decreasing plaque cholesterol content), reduce inflammation at the plaque site, slow progression of coronary artery calcifica- tion, improve abnormal endothelial function, enhance the ability of blood vessels to dilate, reduce the risk of atrial fibrillation, and reduce the risk of thrombosis by (1) inhibiting platelet deposition and aggregation and (2) suppressing production of thrombin, a key factor in clot formation. All of these actions help reduce the risk of CV events.
Increased Bone Formation. There is evidence that statins may promote bone formation and may thereby reduce the risk of osteoporosis and related fractures. This has been shown in several case-control studies in humans.
However, other case-control studies have failed to demonstrate a protective effect. In addition, six randomized controlled trials of statins in 3022 post- menopausal women failed to show a difference in bone density. Until randomized controlled trials are completed in other populations, osteoporosis should be managed with bisphosphonates and/or other drugs with proven efficacy (see Chapter 75).
Mechanism of Cholesterol Reduction
The mechanism by which statins decrease LDL cholesterol levels is complex and depends ultimately on increasing the number of LDL receptors on hepatocytes (liver cells). The process begins with inhibition of hepatic HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. In response to decreased cholesterol production, hepatocytes synthesize more HMG-CoA reductase. As a result, cholesterol synthesis is largely restored to pretreatment levels. However—and for reasons that are not fully understood—inhibition of cholesterol synthesis causes hepatocytes to synthesize more LDL receptors.
As a result, hepatocytes are better able to remove more LDLs from the blood. In patients who are genetically unable to synthesize LDL receptors, statins fail to reduce LDL levels,
Drug
% Change in Serum Lipidsa Effect of CYP3A4
Inhibitors on Statin Levelsb
Effect of Renal or Hepatic Impairment on Statin Levels
LDL-C HDL-C TGs
Atorvastatin
[Lipitor] ↓ 25–60 ↑ 5–15 ↓ 15–50 Moderate ↑ No change with renal disease; significant ↑
with hepatic impairment Fluvastatin [Lescol,
Lescol XL] ↓ 20–40 ↑ 2–11 ↓ 10–25 None No change with renal disease; possible ↑ with
hepatic impairment Lovastatin
[Altoprev, Mevacor]
↓ 20–40 ↑ 5–10 ↓ 5–25 Significant ↑ ↑ with significant renal impairment; no change with hepatic impairment
Pitavastatin [Livalo] ↓ 40–45 ↑ 6–8 ↓ 15–30 Little or none ↑ with significant renal impairment; little or no change with hepatic impairment
Pravastatin
[Pravachol] ↓ 20–40 ↑ 1–15 ↓ 10–25 None Potential ↑ with either renal or hepatic
impairment Rosuvastatin
[Crestor] ↓ 30–60 ↑ 3–20 ↓ 10–40 None ↑ levels with severe renal impairment or
hepatic dysfunction
Simvastatin [Zocor] ↓ 25–50 ↑ 7–15 ↓ 8–40 Significant ↑ Potential ↑ with severe renal or hepatic impairment
TABLE 50.6 ■ HMG-CoA Reductase Inhibitors: Selected Aspects of Clinical Pharmacology
aThe values were obtained from a variety of studies and do not reflect dose dependency of drug responses.
bInhibitors of CYP3A4 (the 3A4 isoenzyme of P450) include itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, cyclosporine, nefazodone, and substances in grapefruit juice.
↑, Increase; ↓, decrease.
HDL-C, High-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TGs, triglycerides.
Obviously, doing so would greatly expand the number of patients receiving statin therapy.
A more recent trial—Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)—reinforced the results of the Heart Protection Study. The study demonstrated that rosuvastatin can reduce the risk of coronary events in people with normal LDL levels, but with high levels of CRP and other risk factors for ASCVD.
Prevention in Patients With Diabetes. Results of the Collaborative Atorvastatin Diabetes Study (CARDS) indicate that statin therapy can reduce the risk of CV events in diabetes patients, even if LDL levels are normal.
This randomized trial, conducted in Britain and Ireland, enrolled 2838 patients with type 2 diabetes who had no history of CV disease. Half received 10 mg of atorvastatin [Lipitor] daily, and half received a placebo. After a mean of 4 years, the combined incidence of acute coronary events, coronary revascu- larization, and stroke was only 5.8% in the atorvastatin group, compared with 9% in the placebo group, representing a 36% reduction in risk. These results suggest that statin therapy could benefit most patients with diabetes, regardless of their LDL level.
Therapeutic Uses
When the statins were introduced, they were approved only for hypercholesterolemia (elevated LDL cholesterol levels) in adults. As understanding of their benefits grew, so has the list of indications. Today the statins have nearly a dozen U.S. Food and Drug Administration (FDA)–approved indications, and these drugs can be prescribed for young patients, as well as for adults. Indications for individual statins are shown in Table 50.7. Major indications are discussed in the sections that follow.
Hypercholesterolemia. Statins are the most effective drugs we have for lowering LDL cholesterol. In sufficient dosage, statins can decrease LDL cholesterol by more than 60%. For many patients, the treatment goal is to drop LDL cholesterol to below 100 mg/dL. For patients at very high CV risk, a target of 70 mg/dL may be appropriate.
Primary and Secondary Prevention of CV Events. As discussed, statins can reduce the risk of CV events (e.g., MI,
therapy provide more CV protection than moderate reductions. In PROVE-IT, 4162 patients with ACS were randomized to either a moderate statin regimen (pravastatin, 40 mg daily) or an intensive statin regimen (atorvastatin, 80 mg daily). The result? LDL levels in the moderate group dropped to 95 mg/
dL, compared with 62 mg/dL in the intensive group. Furthermore, not only did intensive therapy produce a greater decrease in LDL cholesterol, it also produced a greater reduction in adverse outcomes: After 24 months, the incidence of CV events (death, MI, unstable angina, or revascularization) was only 22.4% in the intensive group compared with 26.3% in the moderate group. These results led the ATP III panel to recommend lower target LDL levels in patients at very high CV risk.
Primary Prevention Studies. Two major studies have demonstrated the ability of statins to reduce mortality in people with no previous history of coronary events. In the first trial—the West of Scotland Coronary Prevention Study (WOSCOPS)—6595 men with high cholesterol were given either pravastatin (40 mg/day) or placebo. During an average follow-up of 4.9 years, 4.1% of those taking placebo died, compared with only 3.2% of those taking the statin. The second trial—the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)—enrolled 6605 low-risk patients: men and women with average cholesterol levels (221 mg/dL) and no history of CV events. The subjects were randomly assigned to receive lovastatin (20 to 40 mg/day) or placebo. After an average follow-up of 5.5 years, the incidence of first major coronary events was 5.5% for those taking placebo and 3.5%
for those taking the drug—representing a 36% decrease in risk.
Primary Prevention in Patients With Normal Cholesterol Levels.
The landmark Heart Protection Study, published in 2002, was the first major trial to demonstrate that statins can reduce the risk of major coronary events in people who have normal levels of cholesterol. This double-blind, placebo- controlled trial enrolled 20,536 high-risk British patients: men and women with diabetes, prior MI, stroke, or prior angioplasty. Some had high levels of LDL and total cholesterol; others had normal levels. Subjects were randomly assigned to receive either simvastatin (40 mg/day) or placebo. After 5 years, the incidence of death was 12.9% in the treatment group, compared with 14.7% in the placebo group. Death from ASCVD was reduced by 18%. In addition, simvastatin reduced the risk of nonfatal MI by 38% and of stroke by 25%, and reduced the need for coronary revascularization (e.g., angioplasty) by 30%. Most strikingly, benefits were seen in patients whose LDL cholesterol was normal or low, as well as in those whose levels were high. These data suggest a radical shift in practice. Specifically, they suggest we should treat people at high ASCVD risk—not just those with high cholesterol levels.
Indication Atorvastatin
[Lipitor]
Fluvastatin [Lescol, Lescol XL]
Lovastatin [Altoprev,
Mevacor] Pitavastatin
[Livalo] Pravastatin
[Pravachol] Rosuvastatin
[Crestor] Simvastatin [Zocor]
Primary hypercholesterolemia ✓ ✓ ✓ ✓ ✓ ✓ ✓
Homozygous familial
hyperlipidemia ✓ ✓ ✓
Heterozygous familial hypercholesterolemia in adolescents
✓ ✓ ✓ ✓ ✓
Mixed dyslipidemia ✓ ✓ ✓ ✓ ✓ ✓ ✓
Primary
dysbetalipoproteinemia ✓ ✓ ✓ ✓
Primary prevention of
coronary events ✓ ✓ ✓ ✓a ✓
Secondary prevention of CV
events ✓ ✓ ✓ ✓ ✓
Increasing HDL cholesterol in primary
hypercholesterolemia
✓ ✓ ✓ ✓ ✓
Slowing progression of
coronary atherosclerosis ✓ ✓ ✓ ✓
TABLE 50.7 ■ HMG-CoA Reductase Inhibitors: FDA-Approved Indications
aRosuvastatin is approved for primary prevention in patients who have normal LDL cholesterol and no clinical evidence of ASCVD, but who do have high levels of C-reactive protein combined with other risk factors for CV disease.
and simvastatin—undergo clinically significant (10% to 20%) excretion in the urine.
Three statins—atorvastatin, lovastatin, and simvastatin—are metabolized by CYP3A4 (the 3A4 isoenzyme of cytochrome P450). As a result, levels of these drugs can be lowered by agents that induce CYP3A4 synthesis and speed up the meta- bolic inactivation of the statin. More importantly, statin levels can be increased—sometimes dramatically—by agents that inhibit CYP3A4 (see With Drugs That Inhibit CYP3A4 later in this chapter).
One agent—rosuvastatin—reaches abnormally high levels in people of Asian heritage. At usual therapeutic doses, rosu- vastatin levels in these patients are about twice those in Caucasians. Accordingly, if rosuvastatin is used by Asians, dosage should be reduced.
Adverse Effects
Statins are generally well tolerated. Side effects are uncommon.
Some patients develop headache, rash, memory loss, or GI dis- turbances (dyspepsia, cramps, flatulence, constipation, abdominal pain). However, these effects are usually mild and transient.
Serious adverse effects—hepatotoxicity and myopathy—
are relatively rare. Some statins pose a greater risk than others, as noted here.
Myopathy/Rhabdomyolysis. Statins can injure muscle tissue. Mild injury occurs in 5% to 10% of patients. Charac- teristic symptoms are muscles aches, tenderness, or weakness that may be diffuse or localized to certain muscle groups.
Rarely, mild injury progresses to myositis, defined as muscle inflammation associated with moderate elevation of creatine kinase (CK), an enzyme released from injured muscle. Release of potassium from muscle may cause blood potassium concentra- tions to rise. Rarely, myositis progresses to potentially fatal rhabdomyolysis, defined as muscle disintegration or dissolution.
Release of muscle components leads to marked elevations of blood CK (greater than 10 times the upper limit of normal [ULN]) and elevations of free myoglobin. High levels of CK, in turn, may cause renal impairment, as excess CK can plug up the glomeruli, thereby preventing normal filtration.
Fortunately, fatal rhabdomyolysis is extremely rare: The overall incidence is less than 0.15 case per 1 million prescrip- tions. Nonetheless, patients should be informed about the risk of myopathy and instructed to notify the prescriber if unex- plained muscle pain or tenderness occurs. How statins cause myopathy is unknown.
Several factors increase the risk of myopathy. Among these are advanced age, small body frame, frailty, multisystem disease (e.g., chronic renal insufficiency, especially associated with diabetes), use of statins in high doses, low vitamin D and coenzyme Q levels, concurrent use of fibrates (which can cause myopathy too), and the use of drugs that can raise statin levels (see the following paragraphs). In addition, hypothyroidism increases risk. Accordingly, if muscle pain develops, thyroid function should be assessed. Measurement of CK levels can facilitate diagnosis. Levels should be determined at baseline and again if symptoms of myopathy appear. If the CK level is more than 10 times the ULN, the statin should be discon- tinued. If the level is less than 10 times the ULN, the statin can be continued, provided myopathy symptoms and the CK level are followed weekly. However, given that weekly blood tests are expensive and inconvenient, it may be best to stop the statin and re-evaluate therapy, even when CK levels are angina, stroke) in patients who have never had one (primary
prevention), and they can reduce the risk of a subsequent event after one has occurred (secondary prevention). Risk reduction is related to the reduction in LDL: the greater the LDL reduction, the greater the reduction in risk.
Primary Prevention in People With Normal LDL Levels.
One agent—rosuvastatin [Crestor]—is now approved for reduc- ing the risk of CV events in people with normal levels of LDL and no clinically evident ASCVD, but who do have an increased risk based on advancing age, high levels of high-sensitivity C-reactive protein, and at least one other risk factor for CV disease (e.g., hypertension, low HDL, smoking). Approval for this use was based in large part on results of the JUPITER trial.
Post-MI Therapy. Patients who have survived an MI and who were not on statin therapy at the time of the event are routinely started on a statin, the rationale being “better late than never.” The current trend is to begin statins as soon as the patient is stabilized and able to take oral drugs. Other drugs for MI are discussed in Chapter 53.
Diabetes. Cardiovascular disease is the primary cause of death in people with diabetes. Hence, to reduce mortality, controlling CV risk factors—especially hypertension and high cholesterol—is as important as controlling high blood glucose.
The American Diabetes Association recommends a statin for all patients older than 40 years whose LDL cholesterol is greater than 100 mg/dL. The American College of Physicians recom- mends a statin for (1) all patients with type 2 diabetes plus diagnosed ASCVD—even if they don’t have high cholesterol;
and (2) all adults with type 2 diabetes plus one additional risk factor (e.g., hypertension, smoking, age older than 55 years)—
even if they don’t have high cholesterol. Taken together, these guidelines suggest that most patients with diabetes should receive a statin.
Potential Uses. Potential uses of statins extend well beyond diabetes and CV disorders. Judging from preliminary evidence, these drugs may eventually be used to prevent and/or treat a variety of conditions, including Alzheimer’s disease, kidney disease, multiple sclerosis, macular degeneration, glaucoma, rheumatoid arthritis, weak or brittle bones, and even certain cancers.
Influenza is associated with an increase in the risk for ACS, stroke, and venous thromboembolism. This is related to the increase in proinflammatory cytokines released during influenza.
It is thought that statins can decrease this cytokine release and improve influenza-associated morbidity and mortality. A 10-year retrospective cohort study of older adults revealed that statins can protect against influenza morbidity in people taking statins as an outpatient. It also noted that there was an increase in the mortality of hospitalized patients admitted with influenza when their statin was stopped. Although this information is promising, more research is needed.
Pharmacokinetics
Statins are administered orally. The amount absorbed ranges between 30% and 90%, depending on the drug. Regardless of how much is absorbed, most of an absorbed dose is extracted from the blood on its first pass through the liver, the princi- pal site at which statins act. Only a small fraction of each dose reaches the systemic circulation. Statins undergo rapid hepatic metabolism followed by excretion primarily in the bile. Only four agents—lovastatin, pitavastatin, pravastatin,
and similar results were found. The reason for this association is unknown. The greatest risk appears to be in patients taking simvastatin, lovastatin, and atorvastatin. Overall, the risk remains small, and statin therapy should be continued in patients when indicated.
Drug Interactions
With Other Lipid-Lowering Drugs. Combining a statin with most other lipid-lowering drugs (except probably the bile-acid sequestrants) can increase the incidence and severity of the most serious statin-related adverse events: muscle injury, liver injury, and kidney damage. The increase in risk occurs primarily with fibrates (gemfibrozil, fenofibrate), which are commonly combined with statins. The bottom line: When statins are combined with other lipid-lowering agents, use extra caution and monitor for adverse effects more frequently.
With Drugs That Inhibit CYP3A4. Drugs that inhibit CYP3A4 can raise levels of lovastatin and simvastatin sub- stantially, and can raise levels of atorvastatin moderately, by slowing their inactivation. Important inhibitors of CYP3A4 include macrolide antibiotics (e.g., erythromycin), azole antifungal drugs (e.g., ketoconazole, itraconazole), HIV protease inhibitors (e.g., ritonavir), amiodarone (an antidysrhythmic drug), and cyclosporine (an immunosuppressant). If these drugs are combined with a statin, increased caution is advised. Some authorities recommend an automatic reduction in statin dosage if these inhibitors are used.
As discussed in Chapter 6, chemicals in grapefruit and grapefruit juice can inhibit CYP3A4. Furthermore, the inhibition may persist for 3 days or more after eating the fruit or drinking its juice. Accordingly, statin users should avoid grapefruits and their juice.
Use in Pregnancy
Statins are classified in FDA Pregnancy Risk Category Xb: The risks to the fetus outweigh any potential benefits of treat- ment. Some statins have caused fetal malformation in animal models—but only at doses far higher than those used in humans.
To date, teratogenic effects in humans have not been reported.
Nonetheless, because statins inhibit synthesis of cholesterol and because cholesterol is required for the synthesis of cell membranes as well as several fetal hormones, concern regarding human fetal injury remains. Moreover, there is no compelling reason to continue lipid-lowering drugs during pregnancy:
Stopping the statin for 9 months is not going to cause a sudden, dangerous rise in cholesterol levels or risk of ASCVD. Women of childbearing age should be informed about the potential for fetal harm and warned against becoming pregnant. If pregnancy occurs and the patient plans to continue the pregnancy, statins should be discontinued.
Preparations, Dosage, and Administration
Statins are available alone and in fixed-dose combinations.
The single-ingredient products are discussed here. The combina- tion products are discussed later in the chapter under the heading Drug Combinations.
Seven statins are available for use alone: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, less than 10 times the ULN. Routine monitoring of CK in
asymptomatic patients is unnecessary.
What is the rhabdomyolysis risk with individual statins?
Of the seven statins in current use, rosuvastatin [Crestor] poses the highest risk of rhabdomyolysis. But even with this drug, the absolute number of cases is extremely low. With the other statins, the risk is even lower.
Should concerns about myopathy discourage statin use?
Definitely not! Remember: The risk of serious myopathy is extremely low, whereas the risk of untreated LDL cholesterol is very high. Accordingly, when statins are used to lower cholesterol, the benefits of therapy (reduction of CV events) far outweigh the small risk of myopathy. Additional strategies for the management of myalgia include replacement of vitamin D and coenzyme Q and switching statins. Studies reveal that replacement of vitamin D and coenzyme Q can reduce myalgias in patients with low levels. Switching statins can be effective, as patients may not have myalgias when taking a different drug, even if it is within the same class.
Hepatotoxicity. Liver injury, as evidenced by elevations in serum transaminase levels, develops in 0.5% to 2% of patients treated 1 year or longer. However, jaundice and other clinical signs are rare. Progression to outright liver failure occurs very rarely. Because of the risk of liver injury, product labeling recommends that liver function tests (LFTs) be done before treatment and then if clinically indicated after starting the drug.
If serum transaminase levels rise to 3 times the ULN and remain there, statins should be discontinued. Transaminase levels decline to pretreatment levels following drug withdrawal.
Should statins be used by patients with active liver disease?
The answer depends on the disease. In patients with viral or alcoholic hepatitis, statins should be avoided. However, in patients with the most common cause of hepatitis—nonalcoholic fatty liver disease—statins are acceptable therapy. In fact, in these patients, not only can statins reduce cholesterol levels, they may also decrease liver inflammation, improve LFTs, and reduce steatosis (fatty infiltration in the liver). Should LFTs be monitored? Yes—at baseline and as clinically indicated thereafter. If LFTs climb to 3 times the ULN, statin use should stop.
New-Onset Diabetes. The risk of developing new-onset diabetes while taking a statin is 1 in 500 patients prescribed a statin. Yet many of the patients in these studies had prediabetes before taking a statin. It is unclear whether taking a statin accelerates the advancement from prediabetes to diabetes.
Despite the possibility, the CV benefits of taking a statin far outweigh the risk, and management should not change.
Memory Loss. Some patients have reported reversible memory loss or confusion that improves after stopping statin therapy. Although memory loss may occur, there is an overall lack of evidence surrounding these reports. A large review of 41 different studies completed in 2013 found no connection between memory loss and statin use. What the evidence does reveal is a possible increase in memory loss in patients taking any type of cholesterol-reducing medication, not just statins.
As this issue remains unclear, patients should still report confusion or memory loss to their provider.
Cataracts. An analysis of military healthcare records between 2003 and 2010 revealed a 27% increase of cataracts in patients who had taken a statin for at least 90 days when compared with patients not taking statins. More recently, two larger studies were completed in the older adult population,
bAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.